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AgRP neurons regulate hematopoiesis and Treg generation through beta 3 adrenergic receptor-expressing stromal cells

ABSTRACT: Maturation of hematopoietic stem and progenitor cells (HSPC) in bone marrow (BM) and of T-lymphocytes in thymus occurs within stromal areas innervated by adrenergic fibers of the sympathetic nervous system (SNS). Here we have discovered that in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS), SNS signaling to specific stromal cells expressing beta 3 adrenergic receptors (B3AR) promote differentiation and mobilization of hematopoietic precursors in BM and generation of regulatory T-lymphocytes (Treg) in the thymus. We demonstrate that the functionality of B3AR on BM and thymic stromal cells is under control of hypothalamic neurons expressing Agouti-Related Protein (AgRP), which are activated in EAE. The finding that AgRP neuropeptide is increased in the serum of people with MS, supports that AgRP neurons might be activated also in MS.

ORGANISM(S): Mus musculus

PROVIDER: GSE214765 | GEO | 2022/10/09

REPOSITORIES: GEO

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FoxO1 target Gpr17 activates AgRP neurons to regulate food intake.

Project description:Hypothalamic neurons expressing Agouti-related peptide (AgRP) are critical for initiating food intake, but druggable biochemical pathways that control this response remain elusive. Thus, genetic ablation of insulin or leptin signaling in AgRP neurons is predicted to reduce satiety but fails to do so. FoxO1 is a shared mediator of both pathways, and its inhibition is required to induce satiety. Accordingly, FoxO1 ablation in AgRP neurons of mice results in reduced food intake, leanness, improved glucose homeostasis, and increased sensitivity to insulin and leptin. Expression profiling of flow-sorted FoxO1-deficient AgRP neurons identifies G-protein-coupled receptor Gpr17 as a FoxO1 target whose expression is regulated by nutritional status. Intracerebroventricular injection of Gpr17 agonists induces food intake, whereas Gpr17 antagonist cangrelor curtails it. These effects are absent in Agrp-Foxo1 knockouts, suggesting that pharmacological modulation of this pathway has therapeutic potential to treat obesity. We used microarrays to detail the change of gene expression in AgRP neurons after knocking out FoxO1. AgRP neurons from control and KO mice were collected by FACS. Gene expression was analyzed by microarray.

2013-04-09 | E-GEOD-45858 | biostudies-arrayexpress

Antagonistic modulation of NPY/AgRP and POMC neurons in the arcuate nucleus by noradrenaline

Project description:The arcuate nucleus of the hypothalamus (ARH) is one key structure controlling energy homeostasis. While it has been shown that the biogenic amines dopamine and serotonin modulate food intake controlling NPY/AgRP and/or POMC neurons in the ARH, the neural substrates that mediate the effect of noradrenaline (NA) on energy homeostasis remain elusive. By electrophysiological recordings and cell type-specific transcriptomics we show that the main neuronal populations in the ARH, NPY/AgRP and POMC neurons express a combination of excitatory and inhibitory adrenergic receptors (ARs). Surprisingly, NA had a clear differential effect on these neurons. Activation of NPY/AgRP neurons is mediated by _1A - and _- ARs, while POMC neurons are inhibited via _2A ARs. Collectively, our data indicate an orexigenic influence of NA on the ARH circuitry that controls energy balance

2017-10-26 | GSE106188 | GEO

Liver phosphoproteomics in response to AgRP activated neurons in the presence/absence of NPY

Project description:Autophagy represents a key regulator of aging and metabolism upon cell autonomous sensing of energy deprivation. We find that fasting in mice activates autophagy in liver paralleled by activation of hypothalamic AgRP neurons. Optogenetic and chemogenetic activation of AgRP neurons induces autophagy, alters phosphorylation of autophagy regulators and promotes ß-oxidation in the liver. AgRP neuron dependent induction of liver autophagy relies on NPY expression in these neurons. AgRP neuron projections in the paraventricular nucleus of the hypothalamus (PVH) and the lateral hypothalamus (LHA) mediate AgRP neuron-dependent control of liver autophagy. Conversely, inhibiting AgRP neurons during energy deprivation abrogates induction of hepatic autophagy and re-wiring of metabolism. Finally, AgRP neuron activation increases circulating corticosterone concentrations, and reduction of hepatic glucocorticoid receptor expression attenuates AgRP neuron-dependent activation of hepatic autophagy. Collectively, our study reveals a fundamental regulatory principle of non-cell autonomous control of liver autophagy in control of metabolic adaptation during nutrient deprivation.

2023-04-18 | PXD029247 | Pride

AgRP neurons regulate hematopoiesis and Treg generation through beta 3 adrenergic receptor-expressing stromal cells

Project description:AgRP neurons regulate hematopoiesis and Treg generation through beta 3 adrenergic receptor-expressing stromal cells

| PRJNA887047 | ENA

Analysis of gene expression signatures in brown adipose tissue (BAT) following acute activation of AgRP neurons

Project description:We have found that acute activation of AgRP-neurons lead to inhibition of insulin-stimulated glucose uptake into BAT. Based on this finding, we asked whether this effect was accompanied by acute changes in gene expression, which could point to the mechanism(s) underlying the impaired insulin sensitivity. In summary, our data suggest that activation of AgRP-neurons actuely reprograms gene expression in BAT towards a myogenic profile. The arcuate nucleus of 4 mice expressing channelrhodopsin 2 in AgRP-neurons through Cre-mediated recombination (ChR2-AgRP) and 4 Cre-negative controls (ChR2-fl/WT, Ctrl), were stimulated with blue laser light for one hour, total RNA from BAT was isolated and subjected to a microarray-based gene expression analysis.

2016-02-10 | E-GEOD-77766 | biostudies-arrayexpress

FoxO1 target Gpr17 activates AgRP neurons to regulate food intake.

2013-04-09 | GSE45858 | GEO

Identification of AgRP cells in the murine hindbrain that drive feeding [scRNA-seq]

Project description:Objective: The central melanocortin system is essential for the regulation of food intake and body weight. Agouti-related protein (AgRP) is the sole orexigenic component of the central melanocortin system and is conserved across mammalian species. AgRP is currently known to be expressed exclusively in the mediobasal hypothalamus, and hypothalamic AgRP-expressing neurons are essential for feeding. Here we characterized a previously unknown population of AgRP cells in the mouse hindbrain. Methods: Expression of AgRP in the hindbrain was investigated using gene expression analysis, single-cell RNA sequencing, immunofluorescent analysis and multiple transgenic mice with reporter expressions. Activation of AgRP neurons was achieved by Designer Receptors Exclusively Activated by Designer Drugs (DREADD) and by transcranial focal photo-stimulation using a step-function opsin with ultra-high light sensitivity (SOUL). Results: AgRP expressing cells were present in the area postrema (AP) and the adjacent subpostrema area (SubP) and commissural nucleus of the solitary tract (cNTS) of the mouse hindbrain (termed AgRPHind herein). AgRPHind cells consisted of locally projecting neurons as well as tanycyte-like cells. Food deprivation stimulated hindbrain Agrp expression as well as neuronal activity of subsets of AgRPHind cells. In adult mice that lacked hypothalamic AgRP neurons, chemogenetic activation of AgRP neurons resulted in hyperphagia and weight gain. In addition, transcranial focal photo-stimulation of hindbrain AgRP cells increased food intake in adult mice with or without hypothalamic AgRP neurons. Conclusions: Our study indicates that the central melanocortin system in the hindbrain possesses an orexigenic component, and that AgRPHind neurons stimulate feeding independently of hypothalamic AgRP neurons.

2024-01-23 | GSE204865 | GEO

Reciprocal activity of AgRP and POMC neurons governs coordinated control of feeding and metabolism

Project description:Agouti-related peptide (AgRP)- and proopiomelanocortin (POMC)-expressing neurons reciprocally regulate food intake. Here, we combined non-interacting recombinases to simultaneously express functionally opposing chemogenetic receptors in AgRP and POMC neurons allowing to compare metabolic responses in mice with simultaneous activation of AgRP and inhibition of POMC neurons with isolated activation of AgRP neurons or isolated inhibition of POMC neurons. These experiments revealed that food intake is regulated by the additive effect of AgRP-neuron activation and POMC-neuron inhibition, while systemic insulin sensitivity and gluconeogenesis are differentially modulated by isolated versus simultaneous regulation of AgRP and POMC neurons. We identified a neurocircuit engaging Npy1R-expressing neurons in the paraventricular nucleus of the hypothalamus (PVH), where activated AgRP- and inhibited POMC neurons synergize to promote food consumption and activate neurons in the nucleus tractus solitarii (NTS). We then performed single-nuclei RNA sequencing to define the molecular nature of Fos+ cells in the posterior NTS/AP area that respond to simultaneous chemogenetic intervention over AgRP and POMC neurons and identified TH+ neurons as candidates for receiving neuronal inputs initiated by the simultaneous and coordinated interplay between AgRP and POMC neurocircuits and relayed to the NTS area by the silenced glutamatergic Npy1R neurons.

2024-02-12 | GSE248391 | GEO

AgRP neurons shape the sperm small RNA payload

Project description:Dietary habits and obesity in fathers imprint upon progeny through epigenetic signals carried by sperm RNA. By activating hypothalamic AgRP neurons in mice to mimic obesity's effects, we observed significant alterations in sperm tsRNAs, miRNAs, and rsRNAs. These changes, particularly in tsRNAs, mirror those seen with short-term high-fat diets, suggesting a shared upstream regulatory mechanism involving AgRP neurons that influence metabolic epigenetic inheritance.

2024-10-22 | GSE277621 | GEO

Effects of Klf4 deletion from Agrp expressing cells under chow or HFD conditions

Project description:The goal is to examine the relative abundance of Agrp transcripts and changes to gene expression within the ARC of Agrp-Cre x Klf4-flox KO and control littermates after either regular chow or 10 weeks of HFD

2024-06-03 | GSE225038 | GEO

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